PIEZO1 mediates orthodontic tension force-induced alveolar bone remodeling via the Ca²⁺/YAP-TAZ pathway in periodontal ligament stem cells.

BACKGROUND

Periodontal ligament stem cells (PDLSCs) orchestrate alveolar bone remodeling during orthodontic tooth movement (OTM), yet the molecular mechanism translating tension force into coupled osteogenic and anti-osteoclastic responses remains elusive. This study aimed to define the dual mechanosensitive role of PIEZO1 in PDLSCs for simultaneously promoting osteogenesis and suppressing osteoclastogenesis via the Ca²⁺/YAP-TAZ/OPG-RANKL signaling axis.

METHODS

Human PDLSCs were isolated, characterized for mesenchymal markers, and exposed to cyclic tension (10% strain, 0.5 Hz) using a Flexcell system. PIEZO1 was inhibited using GsMTx4 or siRNA, and Ca²⁺ flux was analyzed by live-cell confocal microscopy. Osteogenic (RUNX2, OSX), osteoclastic (RANKL, OPG), and YAP/TAZ signaling markers were assessed using RT-qPCR and Western blot. For in vivo validation, a rat OTM model was established using 40-g NiTi springs. Tooth movement and tension-side alveolar bone remodeling were quantified by micro-CT, while osteogenic and osteoclastic activities were evaluated through immunohistochemistry and TRAP staining.

RESULTS

Tension force activated PIEZO1 channels, triggering rapid Ca²⁺ influx and subsequent nuclear accumulation of YAP/TAZ. YAP/TAZ activation transcriptionally upregulated RUNX2 and OSX, concurrently reprogramming the PDLSC secretome to favor Osteoprotegerin (OPG) dominance over RANKL, significantly reducing the RANKL/OPG ratio and thus suppressing osteoclast differentiation. Pharmacological inhibition of PIEZO1 (GsMTx4) or genetic knockdown abrogated Ca²⁺ influx, prevented YAP/TAZ nuclear translocation, and disrupted the RANKL/OPG balance, thereby uncoupling osteogenesis from osteoclast suppression both in vitro and in vivo.

CONCLUSIONS

This study defines a fundamental mechanotransduction cascade initiated by PIEZO1, wherein Ca²⁺ influx mobilizes YAP/TAZ nuclear translocation to transcriptionally activate osteogenic differentiation and reprogram anti-osteoclastic secretory profiles. Deciphering this mechanocode nominates PIEZO1 as a promising therapeutic target for recalibrating bone remodeling balance and mitigating pathological bone loss during orthodontic therapy.